Descriptors of multidrug-resistant TB deaths in Ethiopia

Deaths related to multidrug-resistant TB among patients who had received a second-line anti-TB drugs in Ethiopia were analysed. Respectively 38/704 (5.4%) and 44/995 (4.4%) deaths were identified in two cohorts (2015 and 2022). In the 2015 cohort, severe malnutrition was less prevalent, previous treatment rates were three times higher, hypokalaemia was more frequent, and the use of the Xpert® MTB/RIF assay, respiratory failure and severe anaemia/pancytopenia were less common than in the 2022 cohort. We observed that there were variations in adverse events when different treatment regimens were used over different time periods. To ensure proper patient care, correct guidance must be consistently implemented.


Study area, period, population, and data collection procedure
A hospital-based review was conducted in selected high-load RR/MDR-TB treatment initiating centres (TICs).We analysed RR/MDR-TB patient charts and registers using structured checklists to describe the case fatality of RR/MDR-TB, the distribution and magnitude of clinical parameters related to RR/MDR-TB deaths.Data were collected from June 2012 to June 2015 (the 2015 cohort) from Amhara and Oromia Regions; and from July 2020 to June 2022 (the 2022 cohort) from the Oromia, Amhara, Addis Ababa, South Nation and Nationalities and Peoples (SNNP) Regions to compare relevant variables related to TB deaths.Sociodemographic variables (age, sex), HIV status, previous TB treatment and comorbid diseases were some of the variables included in the analysis.All deaths in selected treatment centres were line-listed and their charts were reviewed to get the necessary information.
We conducted descriptive statistical analyses.This review was carried out after obtaining approval for the extraction of the secondary data from the regional ethical clearance committee.

Sociodemographic and clinical characteristics
In the 2015 cohort of patients, a total of 38 MDR/RR-TB deaths out of a total of 704 RR/MDR-TB patients were documented in Oromia and Amhara Regions of the country.In the 2022 cohort of patients, a total of 44 MDR/RR-TB deaths out of a total of 995 RR/MDR-TB patients were registered and reviewed from Addis Ababa, SNNP, Oromia and Amhara.RR/MDR-TB-related death rates were 5.4% in the 2015 cohort and 4.4% in 2022 cohort.In the 2022 cohort, more than 93% of patients had severe form of disease at the time of diagnosis, which may have contributed to early death.Compared to the 2022 cohort, severe malnutrition was less prevalent (odds ratio [OR] 0.24, 95% confidence interval [CI] 0.93-0.63),history of previous treatment was three times higher (OR 2.77, 95% CI 1.05-7.24),electrolyte imbalance (hypokalaemia) was more frequent (28% vs. 3%, Fisher's Exact test,P = 0.001), and Xpert ® MTB/RIF (Cepheid, Sunnyvale, CA, USA) testing (37% vs. 95%, P < 0.001), respiratory failure (3% vs. 29%, Fisher's Exact test, P = 0.013) and severe anaemia/pancytopenia were less common (3% vs. 35%, Fisher's Exact test, P = 0.003) in the 2015 cohort.Early death (within 2 months of treatment initiation) and other factors such as comorbidities (HIV and diabetes mellitus) in the two cohorts were similar (Table ).In the 2022 cohort, 41/44 (93%) of patients who died had severe forms of TB (mainly disseminated TB, miliary TB and extensive bilateral lung disease) at the time of diagnosis (Figure).
In the 2015 cohort, the standard long treatment regimen that included injectables was the predominant treatment regimen, with over 95% of patients receiving it in all TICs across the country.In the 2022 cohort, the all-oral bedaquiline (BDQ) and linezolid (LZD) containing longer treatment regimens were administered to 57% of patients, followed by the short, all-oral, BDQ-containing regimen (23%).The remainder (16%) were on individualised regimens.Only 5% of patients were on injectable-containing treatment regimens.RR/MDR-TB patients were managed in line with Ethiopian national guideline recommendations for the management of RR/ MDR-TB. 2

DISCUSSION
Our review indicates that RR/MDR-TB-related mortality is more prevalent in patients with malnutrition, which has been worsening over time.Malnutrition was observed in individuals with severe disease and typically manifested within the initial months of presentation during the study periods.Almost all patients had severe forms of the disease at the time of diagnosis, which may have contributed to early death.Although the use of molecular diagnostic testing (GeneXpert) has increased, the rate of early deaths remained similar in the two cohorts.4][5][6] We identified variations in adverse events, including the shift from an injectable-based regimen with notable electrolyte imbalances in the 2015 cohort to an all-oral BDQ and LZD-based regimen with a significant occurrence of severe anaemia/pancytopenia in the more recent 2022 cohort.These variations in adverse events are consistent with reports from other countries. 7,8

CONCLUSION
This hospital-based TB mortality review showed severe malnutrition was more prevalent among patients who died of RR/MDR-TB.The persistence of early deaths underscores the need for additional prospective studies to gain a clearer understanding of the underlying causes of these fatalities.Patients experienced adverse events while on treatment, and these varied according to regimen type and the presence of risk factors like severe malnutrition and a history of previous treatment.We strongly recommend adjunctive nutritional care, including therapeutic feeding, for all DR-TB patients as standard of care.We also recommend the use of emergency care management services for RR/MDR-TB patients to prevent early death.Similarly, patients experiencing adverse events including drug toxicities, those with comorbid conditions and risk factors should be managed in consultation with senior experts based on guidelines and global recommendations.We also recommend implementing community awareness programmes that promote psychosocial support and encourage early healthcare-seeking behaviour.Les décès liés à la TB multirésistante chez les patients ayant reçu des médicaments antituberculeux de seconde ligne en Éthiopie ont été analysés.Respectivement 38/704 (5,4%) et 44/995 (4,4%) décès ont été identifiés dans deux cohortes (2015 et 2022).Dans la cohorte 2015, la malnutrition sévère était moins fréquente, les taux de traitement antérieur étaient trois fois plus élevés, l'hypokaliémie était plus fréquente, et l'utilisation du test Xpert ® MTB/RIF, l'insuffisance respiratoire et l'anémie/pancytopénie sévère étaient moins fréquentes que dans la cohorte 2022.Nous avons observé des variations dans les effets indésirables lorsque différents schémas thérapeutiques étaient utilisés sur différentes périodes.Pour garantir des soins adéquats aux patients, des consignes appropriées doivent être appliquées de manière régulière.
Public Health Action (PHA) welcomes the submission of articles on all aspects of operational research, including quality improvements, costbenefit analysis, ethics, equity, access to services and capacity building, with a focus on relevant areas of public health (e.g.infection control, nutrition, TB, HIV, vaccines, smoking, COVID-19, microbial resistance, outbreaks etc).This is an Open Access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0 published by The Union (www.theunion.org).Contact: pha@theunion.orgInformation on PHA: http://www.theunion.org/what-we-do/journals/pha